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151.
Barbier O Duran-Sandoval D Pineda-Torra I Kosykh V Fruchart JC Staels B 《The Journal of biological chemistry》2003,278(35):32852-32860
Glucuronidation, a major metabolic pathway for a large variety of endobiotics and xenobiotics, is catalyzed by enzymes belonging to the UDP-glucuronosyltransferase (UGT) family. Among UGT enzymes, UGT2B4 conjugates a large variety of endogenous and exogenous molecules and is considered to be the major bile acid conjugating UGT enzyme in human liver. In the present study, we identify UGT2B4 as a novel target gene of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha), which mediates the hypolipidemic action of fibrates. Incubation of human hepatocytes or hepatoblastoma HepG2 and Huh7 cells with synthetic PPAR alpha agonists, fenofibric acid, or Wy 14643 resulted in an increase of UGT2B4 mRNA levels. Furthermore, treatment of HepG2 cells with Wy 14643 induced the glucuronidation of hyodeoxycholic acid, a specific bile acid UGT2B4 substrate. Analysis of UGT2B mRNA and protein levels in PPAR alpha wild type and null mice revealed that PPAR alpha regulates both basal and fibrate-induced expression of these enzymes in rodents also. Finally, a PPAR response element was identified in the UGT2B4 promoter by site-directed mutagenesis and electromobility shift assays. These results demonstrate that PPAR alpha agonists may control the catabolism of cytotoxic bile acids and reinforce recent data indicating that PPAR alpha, which has been largely implicated in the control of lipid and cholesterol metabolism, is also an important modulator of the metabolism of endobiotics and xenobiotics in human hepatocytes. 相似文献
152.
HDL and triglyceride as therapeutic targets 总被引:10,自引:0,他引:10
PURPOSE OF REVIEW: Epidemiological studies have shown that plasma HDL-cholesterol is inversely related to coronary artery disease and that there is an inverse relationship between HDL-cholesterol and triglyceride levels, but it is now demonstrated that hypertriglyceridemia is an independent risk factor for coronary heart disease (CHD). The goal of this review is to discuss if triglycerides and HDL-cholesterol could be therapeutic targets to reduce cardiovascular risk. RECENT FINDINGS: Triglyceride measurement is not informative on the specificity of the triglyceride-rich lipoproteins present in the plasma because some of these are not atherogenic (chylomicrons, large VLDLs) while others are highly atherogenic (small VLDLs, remnants, IDL...). Statins, in addition to reducing LDL-cholesterol, significantly reduced atherogenic remnant lipoprotein cholesterol levels. 4S, CARE+LIPID, and AFCAPS/TexCAPS studies, suggested enhanced therapeutic potential of statins for improving triglyceride and HDL-cholesterol levels in patients with CHD. A fibrate (gemfibrozil) was shown to reduce death from CHD and non-fatal myocardial infarction in secondary prevention of CHD in men with low levels of HDL-cholesterol (VA-HIT); during the treatment these levels predicted the magnitude of reduction in risk for CHD events. SUMMARY: ATP III recommendations state, on triglycerides and HDL-cholesterol as targets to reduce cardiovascular risk: (1) that lowering LDL-cholesterol levels is the primary target of therapy, (2) a secondary target is to achieve a triglyceride level < 150 mg/dL and (3) clinical trial data are considered to be insufficient to support recommended a specific HDL-cholesterol goal even if HDL-cholesterol < 40 mg/dL is considered to be a major risk factor of CHD. 相似文献
153.
Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor 总被引:3,自引:0,他引:3
Pineda Torra I Claudel T Duval C Kosykh V Fruchart JC Staels B 《Molecular endocrinology (Baltimore, Md.)》2003,17(2):259-272
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor that controls lipid and glucose metabolism and exerts antiinflammatory activities. PPARalpha is also reported to influence bile acid formation and bile composition. Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that mediates the effects of bile acids on gene expression and plays a major role in bile acid and possibly also in lipid metabolism. Thus, both PPARalpha and FXR appear to act on common metabolic pathways. To determine the existence of a molecular cross-talk between these two nuclear receptors, the regulation of PPARalpha expression by bile acids was investigated. Incubation of human hepatoma HepG2 cells with the natural FXR ligand chenodeoxycholic acid (CDCA) as well as with the nonsteroidal FXR agonist GW4064 resulted in a significant induction of PPARalpha mRNA levels. In addition, hPPARalpha gene expression was up-regulated by taurocholic acid in human primary hepatocytes. Cotransfection of FXR/retinoid X receptor in the presence of CDCA led to up to a 3-fold induction of human PPARalpha promoter activity in HepG2 cells. Mutation analysis identified a FXR response element in the human PPARalpha promoter (alpha-FXR response element (alphaFXRE)] that mediates bile acid regulation of this promoter. FXR bound the alphaFXRE site as demonstrated by gel shift analysis, and CDCA specifically increased the activity of a heterologous promoter driven by four copies of the alphaFXRE. In contrast, neither the murine PPARalpha promoter, in which the alphaFXRE is not conserved, nor a mouse alphaFXRE-driven heterologous reporter, were responsive to CDCA treatment. Moreover, PPARalpha expression was not regulated in taurocholic acid-fed mice. Finally, induction of hPPARalpha mRNA levels by CDCA resulted in an enhanced induction of the expression of the PPARalpha target gene carnitine palmitoyltransferase I by PPARalpha ligands. In concert, these results demonstrate that bile acids stimulate PPARalpha expression in a species-specific manner via a FXRE located within the human PPARalpha promoter. These results provide molecular evidence for a cross-talk between the FXR and PPARalpha pathways in humans. 相似文献
154.
155.
156.
Zoete V Bailly F Vezin H Teissier E Duriez P Fruchart JC Catteau JP Bernier JL 《Free radical research》2000,32(6):515-524
4-Mercaptoimidazoles derived from the naturally occurring family of antioxidants, the ovothiols, were assayed for their antioxidant properties. These compounds are powerful HOCI scavengers, more potent than the aliphatic thiol N-acetylcysteine. They react slowly with hydrogen peroxide with second order rate constants of 0.13-0.89 M-1 s-1. Scavenging of hydroxyl radical occurs at a diffusion-controlled rate (k = 2.0-5.0 × 1010 M-1 s-1) for the most active compounds, which are also able to inhibit copper-induced LDL peroxidation. The combination of radical scavenging and copper chelating properties may explain the inhibitory effects on LDL peroxidation. Two molecules of mercaptoimidazole can chelate a copper ion and form a square planar complex detected by EPR. Compounds bearing an electron-withdrawing group on position 2 of the imidazole ring are the most potent antioxidant molecules in this series. 相似文献
157.
S S Metkar M Marchioretto V Antonini L Lunelli B Wang R JC Gilbert G Anderluh R Roth M Pooga J Pardo J E Heuser M D Serra C J Froelich 《Cell death and differentiation》2015,22(1):74-85
Perforin-mediated cytotoxicity is an essential host defense, in which defects contribute to tumor development and pathogenic disorders including autoimmunity and autoinflammation. How perforin (PFN) facilitates intracellular delivery of pro-apoptotic and inflammatory granzymes across the bilayer of targets remains unresolved. Here we show that cellular susceptibility to granzyme B (GzmB) correlates with rapid PFN-induced phosphatidylserine externalization, suggesting that pores are formed at a protein-lipid interface by incomplete membrane oligomers (or arcs). Supporting a role for these oligomers in protease delivery, an anti-PFN antibody (pf-80) suppresses necrosis but increases phosphatidylserine flip-flop and GzmB-induced apoptosis. As shown by atomic force microscopy on planar bilayers and deep-etch electron microscopy on mammalian cells, pf-80 increases the proportion of arcs which correlates with the presence of smaller electrical conductances, while large cylindrical pores decline. PFN appears to form arc structures on target membranes that serve as minimally disrupting conduits for GzmB translocation. The role of these arcs in PFN-mediated pathology warrants evaluation where they may serve as novel therapeutic targets.The cytotoxic cell granule-secretory pathway depends on perforin (PFN) to deliver granzyme (Gzm) proteases to the cytosol of target cells where they induce apoptosis and other biological effects, such as inflammation.1 Ring-shaped transmembrane PFN pores hereafter called ‘cylindrical pores'', are presumed to act as the gateway for cytosolic entry, either at the plasma membrane or after endocytosis.2, 3, 4 In either case the highly cationic Gzms are thought to diffuse through these cylindrical pores formed by poly-PFN. Nevertheless, a mechanistic understanding of the phenomenon (how the cationic globular protein exchanges from its carrier proteoglycan, serglycin, to the pore and crosses the plasma and/or vesicular membranes) has been lacking due to limitations in imaging technology and in our detailed understanding of the molecular forms that PFN may adopt following interaction with a target cell plasma membrane.Here we show under conditions where cylindrical pore formation is minimal,5 that granzyme B (GzmB) translocation readily occurs. We previously demonstrated that a prelude to granzyme translocation is PFN-mediated, Ca-independent phosphatidylserine (PS) externalization (flip-flop) measured by annexin-V and lactadherin binding.6 This rapid PS flip-flop also occurs when mouse CD8 cells contact antigen-pulsed target cells. Inasmuch as the proteinaceous cylinders offer a formidable barrier to lipid flow, we have speculated that the observed movement of anionic phospholipids to the external leaflet is due to the formation of proteo-lipidic structures, which consists of oligomerized PFN monomers bearing an arc morphology and plasma membrane lipids.6, 7, 8In the work reported here, the topology of PFN embedded into homogeneous planar bilayers and tumor cell plasma membranes was imaged by atomic force microscopy (AFM) and deep etch electron microscopy (DEEM), respectively. Further, the influence of an anti-human PFN mAb (pf-80) that rescues target cells from necrosis,9 was examined. The AFM data show that PFN forms arcs as well as rings in planar bilayers, while conductance measurements across equivalent membranes in parallel experiments measured functional pore sizes consistent with these varied structures. The pf-80 mAb increased the frequency of arc formation and reduced conductance values. Interestingly, PS flip-flop and granzyme delivery were both increased in target cells after PFN oligomerization was interrupted by the pf-80 mAb. A similar effect was seen in T24 bladder carcinoma cells imaged by DEEM. Treatment with PFN leads to deposition of rings (barrel stave pores) and arcs and the pf-80 mAb increased the ratio of arcs to rings on the surface of these cells. We suggest that the observed protein arcs function as toroidal pores in whole cells, explaining PS flip-flop, and act as focal points for granzyme translocation across lipid bilayer. 相似文献
158.
In vivo characterization of human APOA5 haplotypes 总被引:1,自引:0,他引:1
Increased plasma triglyceride concentrations are an independent risk factor for cardiovascular disease. Numerous studies support a reproducible genetic association between two minor haplotypes in the human apolipoprotein A5 gene (APOA5) and increased plasma triglyceride concentrations. We thus sought to investigate the effects of these minor haplotypes (APOA5*2 and APOA5*3) on ApoAV plasma levels through the precise insertion of single-copy APOA5 haplotypes at a targeted location (Hprt) in the mouse genome. While we found no difference in the amount of human plasma ApoAV in mice containing the common APOA5*1 or minor APOA5*2 haplotype, the introduction of the single APOA5*3-defining allele (19W) resulted in three fold lower ApoAV plasma levels, consistent with existing genetic association studies. These results indicate that the S19W polymorphism is likely to be functional and explain the strong association of this variant with plasma triglycerides, supporting the value of sensitive in vivo assays to define the functional nature of human haplotypes. 相似文献
159.
Yamazaki Y Abe K Toma T Nishikawa M Ozawa H Okuda A Araki T Oda S Inoue K Shibuya K Staels B Fruchart JC 《Bioorganic & medicinal chemistry letters》2007,17(16):4689-4693
A combination of benzoxazole, phenoxyalkyl side chain, and phenoxybutyric acids was identified as a highly potent and selective human peroxisome proliferator-activated receptor alpha (PPARalpha) agonist. The synthesis, structure-activity relationship (SAR) studies, and in vivo activities of the representative compounds are described. 相似文献
160.
K Schoonjans J Peinado-Onsurbe J C Fruchart A Tailleux C Fiévet J Auwerx 《FEBS letters》1999,452(3):160-164
Statins are hypolipidemic drugs which not only improve cholesterol but also triglyceride levels. Whereas their cholesterol-reducing effect involves inhibition of de novo biosynthesis of cellular cholesterol through competitive inhibition of its rate-limiting enzyme 3-hydroxy-3-methylglutaryl CoA reductase, the mechanism by which they lower triglycerides remains unknown and forms the subject of the current study. Treatment of normal rats for 4 days with simvastatin decreased serum triglycerides significantly, whereas it increased high density lipoprotein cholesterol moderately. The decrease in triglyceride concentrations after simvastatin was caused by a reduction in the amount of very low density lipoprotein particles which were of an unchanged lipid composition. Simvastatin administration increased the lipoprotein lipase mRNA and activity in adipose tissue and heart. This effect on lipoprotein lipase was accompanied by decreased mRNA as well as plasma levels of the lipoprotein lipase inhibitor apolipoprotein C-III. These results suggest that the triglyceride-lowering effect of statins involves a stimulation of lipoprotein lipase-mediated clearance of triglyceride-rich lipoproteins. 相似文献